A Study Investigating DNA-damage Response Agents in Molecularly Altered Advanced Cancer

Phase 2

Active, not recruiting

Conditions: Advanced Solid Tumours

Interventions: Drug: Ceralasertib

Registration Number: NCT04564027

Lead Sponsor: AstraZeneca

Brief Summary: The study is investigating efficacy, safety and tolerability of DNA-damage Response Agents (or Combinations), in participants with advanced/metastatic solid malignancies whose tumours contain molecular alterations

Detailed Description: Current module of the study will consist of 2 cohorts as follows:

Cohort A (Advanced Solid Tumours \[AST\]): A total of \~25 molecularly eligible and centrally confirmed participants dosed at ceralasertib 160 mg twice daily will be enrolled into this cohort.

Cohort B (Metastatic castration-resistant prostate cancer \[mCRPC\]): A total of \~27 molecularly eligible and centrally confirmed participants dosed at ceralasertib 160 mg twice daily will be enrolled into Cohort B. Unfavourable circulating tumour cells (CTC) count requirement may be introduced for all participants to ensure an adequate (approximately ≥ 50%) number of participants with CTC count ≥ 5/7.5 mL blood.

The screening will have 2 parts, Part 1 and Part 2, which apply for both Cohort A and Cohort B.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 57

Inclusion Criteria

Participants must have a histologically confirmed diagnosis of AST (excluding NSCLC) or mCRPC tumour.
Participants must have a deleterious or suspected deleterious ATM mutation in tumour or blood (germline or ctDNA). Definitions of qualifying ATM mutations may include deleterious/suspected deleterious, pathogenic/likely pathogenic, disease- or cancer-associated variants, or equivalent wording. Variants of unknown significance, benign or likely benign alterations are not qualifying.
Participant must have normal organ and bone marrow function measured within 28 days prior to the first dose of study intervention.
Participants who have no curative treatment options and are deemed appropriate for an investigational study in the opinion of the investigator.
Availability of archival or fresh tumour specimens for central testing of ATM protein loss using immunohistochemistry and for confirmation of ATM mutation using next generation sequencing.
Previously received and progressed on at least one novel hormonal agent (eg, abiraterone acetate, apalutamide, and/or enzalutamide) for the treatment of prostate cancer
Participants with histologically confirmed metastatic castrate resistant prostate cancer.
Documented prostate cancer progression at study entry while on androgen deprivation or after bilateral orchiectomy as assessed by the investigator.
Serum testosterone levels ≤ 50 ng/dL (≤ 1.75 nmol/L) within (≤) 28 days before enrolment.

Exclusion Criteria

Any of the following cardiac diseases currently or within the last 6 months:
1. Unstable angina pectoris.
2. Congestive heart failure > Class 2 as defined by the New York Heart Association
3. Acute myocardial infarction.
4. Significant ventricular or supraventricular arrhythmias.
5. Mean resting corrected QT interval (QTc) > 470 msec obtained from three electrocardiograms (ECGs) in 24 hours using the Fredericia formula.
6. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 years of age.
7. For Cohort B (mCRPC]), surgery or local prostatic intervention (excluding a prostatic biopsy) within 28 days of Cycle 1 Day 1.
Participants with known active infections ((i.e., hepatitis B or C, tuberculosis, or COVID-19).
Participants considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.
Participants with symptomatic and/or uncontrolled brain metastases.
Previous therapy with an telangiectasia and rad3 related protein inhibitor.
Exposure to a small molecule investigational product within 14 days or 5 half-lives.
Concomitant use of known strong CYP 3A inhibitors and inducers.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort A	Ceralasertib	Eligible participants (ATM altered AST), will receive oral dose of Ceralasertib as monotherapy.
Cohort B	Ceralasertib	Eligible participants (ATM altered mCRPC), will receive oral dose of Ceralasertib as monotherapy.

Primary Outcome Measures

Name	Time	Method
Cohort A (aST): Objective Response Rate (ORR).	2 years 4 months	ORR is defined as the percentage of participants who have at least one response of complete response (CR) or partial response (PR) prior to any evidence of progression (as defined by response evaluation criteria in solid tumours \[RECIST\] 1.1) that is confirmed at least 4 weeks later. The CR is defined as disappearance of all target and non-target lesions and no new lesions. The PR is defined as \>= 30% decrease in the sum of the diameters of target lesions compared to baseline and no new non-target lesion. Due to an increased frequency and early onset of Grade≥3 hematological toxicity noted among the participants receiving 240 mg of Ceralsertib, the sponsor decreased the dose to 160mg. Therefore, patients with the 240 mg BID starting dose were not included in the efficacy analyses for both study cohorts.
Cohort B (mCRPC): Composite Response Rate.	Up to 2 years 4 months	Composite response rate is defined as the investigator assessed radiological response by RECIST 1.1 for soft tissue and visceral lesions and Prostate Cancer Working Group 3 (PCWG3) for bone lesions, confirmed prostate specific antigen (PSA) decline of more than 50%, and/or confirmed circulating tumour cell \[CTC\] conversion from unfavorable (\>=5 cells/7.5 ml blood) to favorable (\<5 cells). Due to an increased frequency and early onset of Grade≥3 hematological toxicity noted among the participants receiving 240 mg of Ceralsertib, the sponsor decreased the dose to 160mg. Therefore, patients with the 240 mg BID starting dose were not included in the efficacy analyses for both study cohorts.

Secondary Outcome Measures

Name	Time	Method
Cohort A (aST): Percentage Change in Tumor Size	Scan Visits 1 (Week 8), 2 (Week 16), 3 (Week 24), 4 (Week 32), 5 (Week 40), 6 (Week (48), 7 (Week 56)	Percentage change in tumour size is defined as the reduction from baseline or the increase from baseline in the absence of a reduction in the sum of the longest diameters (or the short axis measurements for lymph nodes) of the target lesions. A negative change denotes a reduction in target lesion size.
Cohort A (aST) and B (mCRPC): Number of Participants With Serious and Non-serious Adverse Events	From Screening (Day -28 to Day -1) Until Follow-up (30 days post last dose), up to 2 years 4 months	The adverse events as a variable of safety and tolerability after admiration of ceralasertib was determined.
Cohort B (mRCPC): Percentage Change in Tumor Size	Scan Visits 1 (Week 8), 2 (Week 16), 3 (Week 24), 4 (Week 32)	Percentage change in tumour size is defined as the reduction from baseline or the increase from baseline in the absence of a reduction in the sum of the longest diameters (or the short axis measurements for lymph nodes) of the target lesions. A negative change denotes a reduction in target lesion size. Due to an increased frequency and early onset of Grade≥3 hematological toxicity noted among the participants receiving 240 mg of Ceralsertib, the sponsor decreased the dose to 160mg. Therefore, patients with the 240 mg BID starting dose were not included in the efficacy analyses for both study cohorts.
Cohort A (aST): Duration of Radiological Response (DoR)	Up to 2 years 4 months	DoR is defined as the time from the date of first documented response (confirmed CR/PR) until date of documented progression or death in the absence of disease progression.
Cohort A (aST): Progression Free Survival (PFS)	Up to 2 years 4 months	PFS is defined as the time from start of study intervention until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraws from therapy or receives another anti-cancer therapy prior to progression. Progression is defined using (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Due to an increased frequency and early onset of Grade≥3 hematological toxicity noted among the participants receiving 240 mg of Ceralsertib, the sponsor decreased the dose to 160mg. Therefore, patients with the 240 mg BID starting dose were not included in the efficacy analyses for both study cohorts.